Insect repellents

ABSTRACT

A number of novel carboxamides have been found to be useful insect repellents.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to insect repellents and more particularly tocertain novel carboxamides containing an alicyclic moiety and their useas insect repellents.

2. Description of the Prior Art

There is a continuing need for insect repellents or formulations thereofthat are significantly more effective or longer lasting than those nowin use. All of the repellents now in use for application to the skinhave disadvantages, that is, they are not effective for long enoughperiods of time and are subject to loss by abrasion, evaporation,absorption, and immersion in water. Moreover, all cause a stingingsensation when they contact the eyelids and lips, and are effective onlywhen they are present on the skin or clothing in relatively largequantities. Mosquitoes, sand flies, black flies, stable flies, tsetseflies, gnats, and tabanids are among the many species of biting fly thatcause annoyance and distress throughout the world. Many species ofbiting insects spread human and animal diseases. There are many areasthroughout the world in both developed and developing nations where theuse of protective clothing and repellents is the only means available toindividuals for personal protection. Deet (N,N-diethyl-m-toluamide) hasproved to be the most outstanding all-purpose individual repellent yetdeveloped (Proceedings of a Symposium, University of Alberta, Edmonton,Canada, May 16-18, 1972, Defense Research Board, Ottawa, Canada, 1973.DR-217: 109-113). Deet was reported as a promising repellent in 1954(Journal of Organic Chemistry, 19, 493, 1954). Since that time, norepellent has been reported as being superior to deet as an all-purposerepellent despite a continuing search for such a chemical.

SUMMARY OF THE INVENTION

An object of this invention is to provide a class of compounds that areuseful as insect repellents.

The above object is accomplished by a number of novel carboxamideshaving from about 11 to about 18 carbon atoms and containing analicyclic moiety. Many of these compounds are more effective thanpresently available repellents and many are effective against a widevariety of insects.

DESCRIPTION OF THE INVENTION

The compounds of this invention are represented by the formula below##STR1## wherein R³ is one of the groups A, B, or C ##STR2## R ishydrogen or lower alkyl, n is zero or the positive integer one, two, orthree, each of R¹ and R² is alkyl, or taken together represent analkylene, an alkenylene, an alkyl substituted alkylene, an alkyleneether, and alkyl substituted alkylene ether, or an alkyl substitutedalkylene amine ring structure.

The compounds of this invention are useful as insect repellents and areparticularly effective against many Dipteran.

The novel compounds of this invention are especially effective inrepelling a wide variety of insects such as ticks, chiggers,cockroaches, and biting diptera such as mosquitoes, stable flies, deerflies, black flies, and sand flies. Certain novel amides reported inthis invention are about equally as effective as deet against mosquitoesand are significantly more repellent than deet against other bitingflies when tested on skin. The skin test is the obvious critical testwhen one considers personal protection; however, clothing repellents arealso very important especially in areas of heavy mosquito infestations(The Journal of the American Medical Association, 196, 253, 1966).Certain amides of this invention provide exceptional protection againstmosquitoes when applied to cloth.

The amides were synthesized as follows: the appropriate acid chloridewas slowly added with stirring to an anhydrous ether solution of theamine cooled in an ice bath (either the amine itself or pyridine wasused as a hydrochloric acid scavenger). The reaction mixture was allowedto warm to room temperature and then allowed to stand for several hours,usually overnight. The amides were isolated by routine extractionprocedures and purified by distillation under high vacuum. Purity waschecked by gas chromatographic analysis.

A typical procedure is illustrated by the following description of thesynthesis of 1-(3-cyclohexenecarbonyl) piperidine, compound 20 in Table1: 3-cyclohexenecarbonyl chloride, 28.9 grams (0.2 mole), was addeddropwise to an ice cold solution (0°-10° C.) of piperidine, 34 grams(0.4 mole) in 250 ml of anhydrous ether. The solution was stirredvigorously during the addition. The reaction mixture was allowed to warmto room temperature and to stand overnight. Water was added to dissolvethe precipitated piperidine hydrochloride salt. The organic layer wasthen washed sequentially with 5% hydrochloric acid and sodiumbicarbonate solutions and finally with a saturated salt solution untilthe wash was neutral to litmus paper and dried over anhydrous magnesiumsulfate. After filtering, the solvent was removed under reduced pressure(water pump). The crude amide was distilled under high vacuum to give31.4 grams of product--b.p. 114°-15° C./0.2 mm Hg), n_(D) ²⁵ 1.5159.

The physical constants of the compounds are presented in Table 1.

The repellent activity of the amides of the present invention wasdemonstrated by practical laboratory and field tests against mosquitoesand a variety of other biting diptera. The effectiveness of therepellents was determined by directly comparing their repellency withthat of deet in tests on skin and with dimethyl phthalate in tests oncloth.

In the following description of the testing procedures the firstconfirmed bite is defined as a bite followed by another within thirtyminutes.

For the purposes of this invention, the compounds were tested as solutesin alcohol, acetone, or other volatile solvent. However, othercompatible liquid or solid carriers may also be used.

TESTING PROCEDURES

STABLE FLIES. The repellents were applied as 1-ml aliquots of a 25%ethanol solution and spread evenly over the forearm of a subject fromwrist to elbow. Since the ethanol solution was formulated on aweight-volume bases, 250 mg of repellent was applied to the forearm ineach test. The most promising compounds (those equal to or better thanthe deet standard at the 25% dosage) were then tested as 12.5% and 6.25%ethanol solutions.

The evaluations were carried out in an outdoor cage (103 cm square and133 cm high) constructed of aluminum and having a solid top and bottomand screen wire on four sides. Four of the sides had port openingscovered with 30.5-cm (12-in.) tubular cloth stockinettes. The centers ofthe ports were 30 cm from the bottom of the cage, which rested on atable 80 cm high. One arm each of up to four treated subjects at a timecould be inserted through the ports into the cage.

Approximately 12,000 S. calcitrans pupae were placed in cups and allowedto emerge in the test cage over an 8-day period. The tests were startedthe 4th day, when approximately 8000 flies had emerged. The remaining4000 that emerged over the next 4 days maintained a relatively stablepopulation in respect to numbers and avidity. Citrated beef blood on acotton pad was offered for 45 minutes each day after the repellent testswere completed. This short-term feeding period provided a small butadequate food intake, and avidity was not reduced as a result ofcomplete engorgement. Results obtained when an untreated forearm wasinserted into the test cage before and during the tests each day gave ameasure of the avidity of the flies, though it was impossible to countthe attacks on the untreated arm.

The effectiveness of each chemical was determined by the protectiontime; that is, the time between treatment and the first confirmed bite.Therefore, 30 minutes after the application of the test chemical andevery 30 minutes thereafter, the treated arms were inserted into thetest cage for 3 minutes unless bites occurred sooner.

Since test subjects differ in attractiveness and insects differ inavidity, the best measure of the effectiveness of a repellent is itsratio of protection time vs. that of a standard repellent used insimilar conditions. Deet was the standard in all of the tests reportedhere. It was paired with each of the other candidate repellents in 10different test series.

The experimental design used was a round-robin series in which eachrepellent was paired concurrently against another repellent on the armsof a subject. An adjusted average protection time that allowed forindividual variation between test subjects and test conditions was thencomputed (Soap and Chemical Specialties, 33, 115-17 and 129-133, 1957).

BLACK FLIES. The principal test site was in the vicinity of Kidney Pond,Baxter State Park, Maine. Meadows bordered by fast moving mountainstreams and an abundance of wildlife provided optimum breedingconditions in this area. Several species of blackflies were representedin the population attacking four test subjects. Of these, the two mostabundant were identified as Simulium venustum Say and Prosimulium mixtumSyme and Davis. Repellents were applied as 1-ml aliquots of a 12.5 or25% ethanol solution and spread evenly over the forearm of a subjectfrom wrist to elbow. The ethanol solution was formulated on aweight-volume bases, so either 125 or 250 mg of repellent was applied ineach test.

Treated arms were continuously exposed to the natural populations offlies. Subjects intermittently moved about with arms raised or on hips,squatted, or sat down for brief periods of 5 to 10 minutes. Thesepositions, coupled with slow walking and standing every few minutes,appeared to be attractive to black flies (Simulids and Prosimulids) andwere used as standard procedure in all tests. Head-net and gloves wereworn by the test subjects to prevent attack on exposed untreated partsof the body.

Two series of round-robin tests were conducted in the spring of 1977using 12.5 or 25% solutions of repellent in ethanol; one series wasconducted during June 1978 using a 25% solution of repellent in ethanol.The effectiveness of each chemical was determined by the protectiontime, i.e., the time between treatment and the first confirmed bite.Since test subjects differ in attractiveness and insects differ inavidity, the best measure of the effectiveness of a repellent is theratio of its protection time to that of a standard repellent undersimilar conditions. Deet was the standard repellent in these tests.

In the round-robin test each repellent was paired with each otherrepellent on the arms of a subject (four or five replicates). Anadjusted average protection time that allowed for individual variationsbetween test subjects and test conditions was then computed. Black flylanding rates ranged from 14 to 40/minute during the test period.

DEER FLIES. The compounds and the standard repellent, deet, were testedon the forearms of human subjects against natural populations of thedeer fly, Chrysops atlanticus. The materials were formulated as 25%ethanol solutions and applied at the rate of 1 ml per forearm. The fieldtests were conducted along logging roads adjacent to the marshes of theOgeechee River at Richmond Hill, Ga., where C. atlanticus populationsoccur in great numbers annually. Since the flies are attracted tomotion, the test subjects continually walked while exposing theirtreated arms to the flies. The tests were terminated when a confirmedbite was received. The chemicals were evaluated in round-robin testswith five compounds and a deet standard in each series. During the3-week test period the landing rate averaged 33 flies/man and rangedfrom 13 to 54/man.

SAND FLIES. Two test sites were used, one at YankeeTown, Florida on theGulf coast and one at Parris Island, S.C. The repellents were applied as25% solutions in ethanol on the forearms (wrist to elbow) of testsubjects. Because of the limited period of insect activity (earlymorning or late afternoon to dusk) the subjects were pretreated 2 hoursprior to the test period to effect aging of the repellents. Therepellents were evaluated against the standard repellent, deet, inpaired tests (3 replications). A test repellent was applied to one armof a subject and deet to the other. Effectiveness was determined by thenumber of bites received during the test period. A control (no repellenttreatment) was included in each test to ascertain the level of insectpressure.

MOSQUITOES. Tests on skin. For laboratory tests, 1 ml of a 25% ethanolsolution of the repellent was spread evenly over the forearm of thesubject. The treated forearms were exposed to about 1500 femalelaboratory reared Aedes aegypti or Anopheles quadrimaculatus mosquitoesin cages. Effectiveness was based on complete protection, that is, thetime between treatment and the first confirmed bite. The effectivenessof the compounds was compared to that of the standard repellent, deet.The chemicals were tested in a round-robin series in a balancedincomplete block design in which each repellent in the series was pairedagainst each other repellent in the series on opposite arms of a givennumber of subjects.

The field tests were conducted at sites adjacent to Mosquito Lagoon nearNew Smyrna Beach, Fl. The repellents were applied in the same manner asfor the laboratory tests. The treated arms were exposed continuously tothe natural population of mosquitoes until the first confirmed bite wasreceived. Protective clothing and head nets were worn by the testsubjects to protect against attack on exposed untreated parts of thebody. The experimental design used was a balanced incomplete block as inthe laboratory tests.

Tests on cloth. Test materials were applied at the rate of 3.3 g ofcompound per 0.1 m² cloth to a measured portion (0.03 m²) of a cottonstocking as 10% solutions in acetone or other volatile solvent. After 2hours, the treated stocking was placed over an untreated nylon stockingon the arm of a human subject and exposed for 1 minute in a cagecontaining about 1500 five- to eight-day old A. aegypti or A.quadrimaculatus. The test exposure was repeated at 24 hours and then atweekly intervals until five bites were received in 1 minute. Days to thefirst bite and to five bites were recorded. Between tests, the treatedstockings were placed on a rack at room temperature, and evaporation wasallowed to continue. A standard repellent, dimethyl phthalate, wastested concurrently and was effective for 11 to 21 days against bothmosquito species.

The merits of the present invention are illustrated in the results shownin the tables.

The data in Table 2 show compounds 2, 7, 20, 33, 34, 47, and 49 weremore active against the stable fly than the deet standard at allconcentrations tested. Compounds 20 and 34 were significantly moreeffective than deet at all three dosages (0.05% level of confidence).Compounds 21 and 35 were more active than deet at two concentrations andequal to it at the lowest concentration tested. The repellent effect ofcertain of these chemicals was as much as 4.5×that of deet and providedprotection up to 9 hours; the protection time of deet ranged from 2 to 3hours. Data for compounds 4, 6, 17, 18, 19, 31, and 45 are shown toillustrate the unpredictability of repellent activity of closely relatedchemicals.

The data in Table 3 show all eight compounds and deet are very goodblack fly repellents. Compound 21 is significantly more effective thandeet at the 25% dosage providing about 10.5 hours protection. There isno significant difference between the remaining compounds and deet atthe 25% dosage. Although not significantly more effective than deet, theadjusted mean for compound 20 was 0.5 and 1.5 hours greater than that ofdeet at the two test dosages. Compounds 7 and 35 provided about 7 hoursprotection; compounds 20 and 47 provided over 8 hours protection;compounds 6 and 33 provided about 9 hours protection.

The data in Table 4 show 10 compounds that exceeded deet in repellencyagainst deer flies. Compound 20 was significantly more effective thandeet with an adjusted mean protection time of 6.3 hours.

The data in Table 5 show compounds 2, 7, 20, and 35 greatly superior todeet in tests conducted in Florida against the sand fly Culicoidesmississippiensis. Compounds 2 and 20 were also superior to deet in theParris Island tests against Culicoides hollensis. Deet is considered agood repellent for sand flies (Meditsinskaya Parazitologiya iParazitarnye Bolezni, 35 (5), 549, 1963). A biting rate of about 5/hourwould make the presence of sand flies tolerable to most people (Journalof Economic Entomology, 64 (1), 264, 1971). The data show certaincompounds of this invention equalling or exceeding this criteria in onetest and equalling or closely approaching it in the second test. Thenumber of bites experienced by the check, clearly shows very high insectpressure during these tests, emphasizing the effectiveness of therepellents.

The data in Table 6 show the relative repellency of compounds of thisinvention against mosquitoes when applied to skin in laboratory andfield tests. Deet is an excellent mosquito repellent (The Journal of theAmerican Medical Association, 196, 253, 1966). Repellents 33 and 34 wereabout equally as effective against Aedes aegypti as deet; repellents 19,20, 21, and 34 were about equally as effective against Anophelesquadrimaculatus as deet. In field tests, repellents 2 and 20 were 1.5and 1.4 times as effective as deet against Aedes taeniorhynchus and 4,6, 7, 21, 33, and 47 were about equally as effective as deet. Becausedeet is such an effective mosquito repellent, chemicals having 0.5ratios to deet are considered good mosquito repellents.

The data in Table 7 show 91 of the repellents were more effective thanthe standard against one species of mosquito and 9 other compounds wereabout equally as effective as the standard. Repellents 91, 100, 101, and115 provided outstanding protection of over 200 days and 29 otherrepellents provided exceptional protection of over 100 days against onespecies or the other. All chemicals providing 11 or more days protectionare considered promising repellents.

The foregoing examples of repellent action of these novel amides againstspecific insect pests is meant to be illustrative rather than limiting.For example, the compounds of the present invention can be mixed withinert ingredients or with other known insect repellents. The compoundsmay also be formulated or embodied into repellent compositions in theform of creams, lotions, emulsions, suspensions, solutions, dusts, andaerosol or other type of sprays.

Although insect repellents are usually applied to the skin, thecompounds of this invention and formulations containing them are alsouseful when applied to clothing, netting, packaging, shippingcontainers, animals, and growing plants.

                                      TABLE 1                                     __________________________________________________________________________    Physical constants of compounds synthesized in accordance with the            procedures of this invention                                                   No.                                                                              ##STR3##     or m.p. (°C.)B.p. (°C./mmHg)Physical                           constants                                                                               n.sub.D.sup.25                                                                     No.                                                                                ##STR4##       or m.p.                                                                      (°C.)B.p.                                                              (°C./mmHg)Physica                                                      l constants                                                                             n.sub.D.sup.25    __________________________________________________________________________     ##STR5##                                                                     1  N,N-Dimethylamino                                                                          69-70/0.45                                                                             1.4794                                                                             9    4-Methyl-1-piperidyl                                                                         113-14/0.8                                                                             1.4970             2  N,N-Dipropylamino                                                                          93-5/0.45                                                                              1.4685                                                                             10   2-Ethyl-1-piperidyl                                                                          131/1.5  1.4970             3  N,N-Dibutylamino                                                                           133/1.5  1.4675                                                                             11   2,6-Dimethyl-1-piperidyl                                                                     109-11/0.5                                                                             1.4950             4  1-Pyrrolidyl 67-8          12   1,2,3,6-Tetrahydro-1-                                                         pyridinyl      107-9/0.5                                                                              1.5175             5  1-Piperidyl  108/0.45 1.5030                                                                             13   4-Methyl-1-piperazinyl                                                                       100-2/0.1                                                                              1.5041             6  1-Hexahydro-1H-azepinyl                                                                    120/0.25 1.5038                                                                             14   4-Morpholinyl  57-8                        7  2-Methyl-1-piperidyl                                                                       110-13/0.7                                                                             1.5001                                                                             15   2,6-Dimethyl-4-morpholinyl                                                                   116-17/0.3                                                                             1.4919             8  3-Methyl-1-piperidyl                                                                       114-16/0.45                                                                            1.4974                                                ##STR6##                                                                     16 N,N-Dimethylamino                                                                          75-6/0.4 1.4960                                                                             24   4-Methyl-1-piperidyl                                                                         110-12/0.15                                                                            1.5087             17 N,N-Dipropylamino                                                                          88/0.15  1.4804                                                                             25   2-Ethyl-1-piperidyl                                                                          114-15/0.1                                                                             1.5068             18 N,N-Dibutylamino                                                                           103/0.1  1.4775                                                                             26   2,6-Dimethyl-1-piperidyl                                                                     112-13/0.1                                                                             1.5055             19 1-Pyrrolidyl 44-5          27   1,2,3,6-Tetrahydro-1-                                                         pyridinyl      114-16/0.45                                                                            1.5315             20 1-Piperidyl  114-15/0.2                                                                             1.5159                                                                             28   4-Methyl-1-piperazinyl                                                                       112-14/0.1                                                                             1.5181             21 1-Hexahydro-1H-azepinyl                                                                    105-6/0.15                                                                             1.5151                                                                             29   4-Morpholinyl  114-16/0.25                                                                            1.5194             22 2-Methyl-1-piperidyl                                                                       110-12/0.1                                                                             1.5106                                                                             30   2,6-Dimethyl-4-morpholinyl                                                                   115-16/0.4                                                                             1.5043             23 3-Methyl-1-piperidyl                                                                       108-10/0.1                                                                             1.5087                                                ##STR7##                                                                     31 N,N-Dipropylamino                                                                          100/0.7  1.4682                                                                             38   4-Methyl-1-piperidyl                                                                         108/0.8  1.4908             32 N,N-Dibutylamino                                                                           126/0.9  1.4669                                                                             39   2-Ethyl-1-piperidyl                                                                          175-8/18 1.4930             33 1-Pyrrolidyl 95/0.25  1.4941                                                                             40   2,6-Dimethyl-1-piperidyl                                                                     108-10/0.5                                                                             1.4905             34 1-Piperidyl  104-6/0.5                                                                              1.4970                                                                             41   1,2,3,6-Tetrahydro-1-                                                         pyridinyl      118-20/1.3                                                                             1.5100             35 1-Hexahydro-1H-azepinyl                                                                    115-18/0.9                                                                             1.5000                                                                             42   4-Methyl-1-piperazinyl                                                                       120-2/1.0                                                                              1.4990             36 2-Methyl-1-piperidyl                                                                       141-3/0.25                                                                             1.4930                                                                             43   4-Morpholinyl  108-9/0.4                                                                              1.4975             37 3-Methyl-1-piperidyl                                                                       168- 70/18                                                                             1.4909                                                                             44   2,6-Dimethyl-4-morpholinyl                                                                   75-7                         ##STR8##                                                                     45 N,N-Dipropylamino                                                                          108/2.0  1.4794                                                                             52   4-Methyl-1-piperidyl                                                                         122-4/1.0                                                                              1.5020             46 N,N-Dibutylamino                                                                           120/0.45 1.4765                                                                             53   2-Ethyl-1-piperidyl                                                                          116-18/0.5                                                                             1.5036             47 1-Pyrrolidyl 133-6/0.2                                                                              1.5082                                                                             54   2,6-Dimethyl-1-piperidyl                                                                     155-17/0.5                                                                             1.5017             48 1-Piperidyl  109/0.5  1.5090                                                                             55   1,2,3,6-Tetrahydro-1-                                                         pyridinyl      113-15/0.7                                                                             1.5234             49 1-Hexahydro-1H-azepinyl                                                                    135/0.9  1.5116                                                                             56   4-Methyl-1-piperazinyl                                                                       105-7/0.3                                                                              1.5106             50 2-Methyl-1-piperidyl                                                                       120-2/1.1                                                                              1.5049                                                                             57   4-Morpholinyl  104-5/0.2                                                                              1.5115             51 3-Methyl-1-piperidyl                                                                       120-2/1.3                                                                              1.5035                                                                             58   2,6-Dimethyl-4-morpholinyl                                                                   122-5/0.4                                                                              1.4990              ##STR9##                                                                     59 N,N-Dipropylamino                                                                          93-5/0.2 1.4900                                                                             66   4-Methyl-1-piperidyl                                                                         98-100/0.1                                                                             1.5163             60 N,N-Dibutylamino                                                                           100-2/0.1                                                                              1.4862                                                                             67   2-Ethyl-1-piperidyl                                                                          108-9/0.15                                                                             1.5168             61 1-Pyrrolidyl 105-8/0.15                                                                             1.5262                                                                             68   2,6-Dimethyl-1-piperidyl                                                                     100-1/0.15                                                                             1.5166             62 1-Piperidyl  111-13/0.2                                                                             1.5244                                                                             69   1,2,3,6-Tetrahydro-1-                                                         pyridinyl      110/0.1  1.5401             63 1-Hexahydro-1H-azepinyl                                                                    121-2/0.4                                                                              1.5262                                                                             70   4-Methyl-1-piperazinyl                                                                       103-4/0.1                                                                              1.5253             64 2-Methyl-1-piperidyl                                                                       108-9/0.2                                                                              1.5197                                                                             71   4-Morpholinyl  99-100/0.1                                                                             1.5258             65 3-Methyl-1-piperidyl                                                                       110-12/0.3                                                                             1.5169                                                                             72   2,6-Dimethyl-4-morpholinyl                                                                   100-2/0.1                                                                              1.5113              ##STR10##                                                                    73 N,N-Dimethylamino                                                                          87-8/0.45                                                                              1.4780                                                                             81   4-Methyl-1-piperidyl                                                                         121/0.5  1.4935             74 N,N-Dipropylamino                                                                          108-9/0.45                                                                             1.4708                                                                             82   2-Ethyl-1-piperidyl                                                                          122-4/0.2                                                                              1.4943             75 N,N-Dibutylamino                                                                           139/0.75 1.4698                                                                             83   2,6-Dimethyl-1-piperidyl                                                                     121-3/0.3                                                                              1.4942             76 1-Pyrrolidyl 110-12/0.25                                                                            1.4977                                                                             84   1,2,3,6-Tetrahydro-1-                                                         pyridinyl      122-4/0.15                                                                             1.5114             77 1-Piperidyl  109-11/0.2                                                                             1.5000                                                                             85   4-Methyl-1-piperazinyl                                                                       109/0.15 1.5016             78 1-Hexahydro-1H-azepinyl                                                                    114-16/0.2                                                                             1.5019                                                                             86   4-Morpholinyl  68-70                       79 2-Methyl-1-piperidyl                                                                       105-7/0.2                                                                              1.4945                                                                             87   2,6-Dimethyl-4-morpholinyl                                                                   125-7/0.5                                                                              1.4892             80 3-Methyl-1-piperidyl                                                                       118/0.4  1.4942                                                ##STR11##                                                                    88 N,N-Dimethylamino                                                                          100-2/0.4                                                                              1.4782                                                                             96   4-Methyl-1-piperidyl                                                                         136-7/0.5                                                                              1.4919             89 N,N-Dipropylamino                                                                          117-18/0.45                                                                            1.4715                                                                             97   2-Ethyl-1-piperidyl                                                                          126-7/0.1                                                                              1.4938             90 N,N-Dibutylamino                                                                           133-5/0.4                                                                              1.4701                                                                             98   2,6-Dimethyl-1-piperidyl                                                                     135/0.35 1.4895             91 1-Pyrrolidyl 126-7/0.2                                                                              1.4928                                                                             99   1,2,3,6-Tetrahydro-1-                                                         pyridinyl      134-5/0.5                                                                              1.5070             92 1-Piperidyl  129- 31/0.2                                                                            1.4950                                                                             100  4-Methyl-1-piperazinyl                                                                       139-40/0.1                                                                             1.4966             93 1-Hexahydro-1H-azepinyl                                                                    131-4/0.3                                                                              1.4985                                                                             101  4-Morpholinyl  122-4/0.1                                                                              1.4961             94 2-Methyl-1-piperidyl                                                                       128-30/0.35                                                                            1.4933                                                                             102  2,6-Dimethyl-4-morpholinyl                                                                   123-5/0.1                                                                              1.4876             95 3-Methyl-1-piperidyl                                                                       136-8/0.5                                                                              1.4912                                                ##STR12##                                                                    103                                                                              N,N-Dimethylamino                                                                          109-10/0.4                                                                             1.4764                                                                             111  4-Methyl-1-piperidyl                                                                         145-7/0.45                                                                             1.4875             104                                                                              N,N-Dipropylamino                                                                          128-30/0.4                                                                             1.4712                                                                             112  2-Ethyl-1-piperidyl                                                                          145/0.25 1.4910             105                                                                              N,N-Dibutylamino                                                                           148/0.4  1.4705                                                                             113  2,6-Dimethyl-1-piperidyl                                                                     151-3/0.5                                                                              1.4874             106                                                                              1-Pyrrolidyl 137-9/0.4                                                                              1.4905                                                                             114  1,2,3,6-Tetrahydro-1-                                                         pyridinyl      145-6/0.45                                                                             1.5035             107                                                                              1-Piperidyl  139-40/0.5                                                                             1.4920                                                                             115  4-Methyl-1-piperazinyl                                                                       134-5/0.15                                                                             1.4975             108                                                                              1-Hexahydro-1H-azepinyl                                                                    153-4/0.5                                                                              1.4940                                                                             116  4-Morpholinyl  149-51/0.45                                                                            1.4932             109                                                                              2-Methyl-1-piperidyl                                                                       142-3/0.45                                                                             1.4909                                                                             117  2,6-Dimethyl-4-morpholinyl                                                                   145-7/0.45                                                                             1.4828             110                                                                              3-Methyl-1-piperidyl                                                                       143-5/0.5                                                                              1.4882                                               __________________________________________________________________________

                  TABLE 2                                                         ______________________________________                                        Repellency of compounds to the stable fly Stomoxy                             calcitrans when applied to the skin at various concentrations                 in ethanol and compared to deet as a test standard                                     Protection time                                                               (minutes)                                                                  %                  Adjusted                                                                              Ratio to                                                                              No. of                               No.   Conc.    Range     mean    deet.sup.a                                                                            tests                                ______________________________________                                        2     6.25     30-90     55      1.7     3                                          12.5     300-360   315     4.50.sup.b                                                                            5                                          25.0     210-463   321     2.02.sup.b                                                                            5                                    4     25.0      30-270   103     0.4     5                                    6     25.0      30-268   183     0.71    5                                    7     25.0     120-300   246     2.01.sup.b                                                                            4                                    17    25.0     180-360   225     0.85    5                                    18    25.0      30-189   122     0.46    5                                    19    25.0      90-420   237     1.0     5                                    20    6.25      30-120   103     2.5.sup.b                                                                             3                                          12.5      60-240   128     2.4.sup.b                                                                             4                                          25.0     360-390   387     2.39.sup.b                                                                            5                                    21    6.25     30-60     33      1.0     5                                          12.5     270-450   306     1.42    5                                          25.0     300-510   457     3.78.sup.b                                                                            4                                    31    25.0     30-60     36      0.2     5                                    33    6.25      60-180   80      1.6     3                                          12.5      90-210   150     3.3.sup.b                                                                             4                                          25.0     240-270   266     1.6     4                                    34    6.25      30-120   118     2.4.sup.b                                                                             3                                          12.5     270-330   320     4.57.sup.b                                                                            5                                          25.0     390-510   419     2.6.sup.b                                                                             4                                    35    6.25     30-30     30      1.0     5                                          12.5     210-375   326     3.27.sup.b                                                                            5                                          25.0     390-510   459     2.9.sup.b                                                                             4                                    36    25.0      30-120   101     1.43    5                                    45    25.0      30-180   78      0.44    5                                    47    6.25     30-90     63      1.9     3                                          12.5     120-270   230     3.29.sup.b                                                                            5                                          25.0     150-405   264     1.66    5                                    49    6.25     30-60     38      1.15    5                                          12.5     150-330   306     1.42    5                                          25.0     480-510   538     3.02.sup.b                                                                            5                                    50    25.0      60-150   125     1.41    5                                    ______________________________________                                         .sup.a Data compiled from a number of different tests, accounting for the     fluctuation between protection time and ratio to deet among the members o     the series.                                                                   .sup.b Significantly different from deet at the 0.05% level of confidence

                  TABLE 3                                                         ______________________________________                                        Repellency of compounds applied to the skin as 12.5 and/or                    25% ethanol solutions compared with deet against                              blackflies in two series of field tests                                                   Protection time                                                              (min)                                                                       %                Adjusted                                                                             Ratio to                                                                             No. of                                No.      Conc.   Range    mean   deet   tests                                 ______________________________________                                        Test I (1977)                                                                 Deet (Std)                                                                             12.5    145-283  161    1.00   5                                              25.0    287-511  426    1.00   4                                     20       12.5    123-314  193    1.20.sup.a                                                                           5                                              25.0    413-565  505    1.19.sup.a                                                                           4                                      7       12.5     26-222  95     0.59   5                                              25.0    309-515  424    1.00.sup.a                                                                           4                                     35       12.5     24-126  93     0.58   5                                              25.0    342-542  412    0.97.sup.a                                                                           4                                      2       12.5     25-112  71     0.44   5                                              25.0    198-375  314    0.74.sup.a                                                                           4                                     ______________________________________                                        Test II (1978)                                                                Deet (Std)                                                                             25.0    399-623  520    1.00   5                                      6       25.0    411-628  537    1.03.sup.a                                                                           5                                     21       25.0    524-725  632    1.21.sup.b                                                                           5                                     33       25.0    498-603  554    1.07.sup.a                                                                           5                                     47       25.0    425-649  486    0.94.sup.a                                                                           5                                     ______________________________________                                         .sup.a Not significantly different from deet at the 0.05% level of            confidence.                                                                   .sup.b Significantly different from deet at the 0.05% level of confidence

                  TABLE 4                                                         ______________________________________                                        Repellency of compounds applied to the skin as                                25% ethanol solutions and compared with deet against                          deerflies in field tests (Avg. of 5 tests)                                    Protection time (min)                                                                                          Ratio to                                     No.     Range      Adjusted mean deet.sup.a                                   ______________________________________                                        2       10-178     133           3.00                                         4       4-77       23            0.51                                         6       10-173     75            1.69                                         17      15-143     62            1.39                                         18      6-36       40            0.89                                         20      363-421    380           5.83.sup.b                                   21      91-203     91            1.1                                          31      10-44      45            0.62                                         34      20-408     141           1.8                                          35      42-182     119           1.5                                          36      5-17       15            0.94                                         45       4-110     18            0.24                                         47      40-160     138           1.89                                         49      37-244     129           1.76                                         50       8-138     27            1.11                                         ______________________________________                                         .sup.a Data compiled from a number of tests, accounting for the               fluctuation between the protection time and ratio to deet among the           members of the series.                                                        .sup.b Significantly different from deet at the 0.05% level of confidence

                  TABLE 5                                                         ______________________________________                                        Repellency of compounds applied to the skin                                   as 25% ethanol solutions and compared with deet                               against the sandflies Culicoides mississippiensis                             and Culicoides hollensis in field tests                                       Compounds    Average       Average                                            paired       bites/test    bites/hour                                         ______________________________________                                        Tests at Yankee Town, Fla. (Avg. 3 tests)                                     Deet         29.0          19.2                                               2            3.33          2.4                                                Deet         31.67         21.0                                               20           5.0           3.6                                                Deet         106.0         70.8                                               35           6.67          4.2                                                Deet         45.0          30.0                                               7            10.0          6.6                                                Check        1299          865.8                                              ______________________________________                                        Tests at Parris Island, S. C. (Avg. 3 tests)                                  Deet         28.67         18.6                                               20           9.33          6.0                                                Deet         85.0          54.6                                               2            16.33         10.8                                               Deet         12.0          7.8                                                7            16.67         10.8                                               Check        1566          1277.4                                             ______________________________________                                    

                  TABLE 6                                                         ______________________________________                                        Repellency of compounds to mosquitoes when applied                            to the skin as 25% ethanol solutions                                          Ratio to deet                                                                 Laboratory test        Field test                                                    Aedes     Anopheles     Aedes                                          No.    aegypti   quadrimaculatus                                                                             taeniorhynchus                                 ______________________________________                                        2      0.22      0.28          1.5                                            4      0.22      0.11          0.77                                           6      0.14      0.74          0.82                                           7      0.70      0.11          1.15                                           17     0.24      0.33          0.52                                           18     0.13      0.05          0.07                                           19     0.20      0.73          0.44                                           20     0.68      1.0           1.4                                            21     0.64      0.86          0.7                                            31     0.24      0.08          0.45                                           33     1.12      0.86          0.69                                           34     0.89      1.0           0.34                                           45     0.23      0.11          0.12                                           47     0.28      0.24          0.99                                           49     0.55      0.09          0.65                                           ______________________________________                                    

                  TABLE 7                                                         ______________________________________                                        Repellency of compounds to mosquitoes in tests on cloth                       Aedes aegypti       Anopheles quadrimaculatus                                 Days to             Days to                                                   No.     1st bite  5 bites   1st bite                                                                              5 bites                                   ______________________________________                                        2       15        15        8       8                                         4       30        38        38      79                                        5       30        38        30      30                                        6       106       113       22      38                                        7       104       104       111     111                                       8       104       104       22      22                                        9       52        104       0       22                                        10      104       104       1       22                                        11      104       104       1       37                                        12      15        15        15      15                                        13      7         15        7       111                                       14      0         1         27      27                                        15      15        28        35      35                                        17      15        15        15      5                                         18      0         30        0       1                                         19      28        28        70      94                                        20      21        28        28      48                                        21      64        87        70      70                                        22      69        69        83      83                                        23      36        36        36      51                                        24      20        20        83      83                                        25      83        83        83      83                                        26      36        36        36      36                                        27      36        36        63      63                                        28      28        28        63      83                                        29      0         0         35      35                                        30      8         8         22      22                                        31      15        15        1       1                                         33      21        28        28      28                                        34      21        28        13      13                                        35      28        28        6       6                                         36      23        43        0       0                                         37      23        51        0       0                                         38      36        36        21      21                                        39      51        71        0       0                                         40      1         23        0       0                                         41      8         15        8       8                                         42      1         1         36      50                                        43      36        77        64      71                                        44      28        28        15      15                                        45      27        27        1       1                                         47      27        27        1       1                                         48      33        41        1       1                                         49      27        47        1       1                                         50      23        51        0       23                                        51      36        36        0       21                                        52      36        36        8       36                                        55      15        15        0       1                                         57      8         22        36      105                                       58      1         28        22      22                                        59      1         35        49      49                                        61      34        55        28      28                                        62      70        70        70      91                                        63      70        128       0       111                                       64      70        70        0       76                                        65      35        70        0       49                                        66      70        70        0       77                                        67      21        34        47      47                                        68      1         28        20      20                                        69      28        28        20      20                                        70      28        28        47      47                                        71      0         0         47      47                                        72      0         34        20      190                                       74      0         0         28      28                                        76      108       108       21      119                                       77      28        108       28      28                                        78      21        130       1       8                                         79      28        102       0       0                                         80      28        102       0       0                                         81      28        51        8       8                                         82      0         28        8       8                                         83      101       108       108     108                                       84      8         28        28      28                                        85      0         105       134     175                                       86      0         1         1       18                                        87      0         105       126     126                                       88      21        21        24      24                                        91      169       169       238     238                                       92      29        29        7       182                                       93      21        65        21      44                                        94      7         21        1       1                                         95      7         21        1       126                                       97      0         12        0       12                                        98      0         21        126     126                                       99      0         12        0       93                                        100     7         7         21      268                                       101     61        133       238     238                                       102     61        93        133     133                                       103     42        42        24      54                                        106     61        160       160     160                                       107     0         36        36      36                                        108     22        22        36      134                                       110     0         1         36      36                                        111     0         0         52      94                                        112     13        13        36      104                                       113     0         1         134     134                                       114     0         36        134     134                                       115     0         51        310     318+                                      116     77        134       134     134                                       117     22        22        134     134                                       ______________________________________                                         *Compound still in test.                                                 

We claim:
 1. An insect repellent of the formula ##STR13## wherein R³ isone of the groups A, B, or C ##STR14## wherein R is hydrogen or loweralkyl, and n is zero or the positive integer one, two, or three, saidrepellent being formulated in a suitable carrier at an effectiverepellent concentration.
 2. A repellent effective against the stablefly, the blackfly, and the deerfly, said repellent having the formula##STR15## and said repellent being formulated in a suitable carrier atan effective repellent concentration.
 3. A repellent effective atainstthe stable fly, the blackfly, the sandfly, and the deerfly, saidrepellent having the formula ##STR16## and said repellent beingformulated in a suitable carrier at an effective repellentconcentration.
 4. A repellent effective against the stable fly and thedeerfly, said repellent having the formula ##STR17## and said repellentbeing formulated in a suitable carrier at an effective repellentconcentration.
 5. An insect repellent effective against the stable fly,the blackfly, and the deerfly, said repellent having the general formula##STR18## wherein R³ is one of the groups A or B ##STR19## wherein R ishydrogen or lower alkyl, said repellent being formulated in a suitablecarrier at an effective repellent concentration.
 6. An insect repellenteffective against the mosquito species, Aedes aegypti and Anophelesquadrimaculatus, said repellent having the formula ##STR20## and saidrepellent being formulated in a suitable carrier at an effectiverepellent concentration.